The general term “pain” is defined here to represent all categories including: traumatic pain resulting from tissue injury, post-surgical pain, burn pain, inflammatory pain; pain associated with disease such as cancer, AIDS, arthritis, herpes, migraine; pain associated with nerve damage or neuropathy, such as diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, fibromyalgia, gout, and other forms of neuralgic, neuropathic and idiopathic pain syndromes; and specific organ or tissue pain, such as ocular and corneal pain, bone pain, heart pain, skin pain, visceral (kidney, gall bladder, gastrointestinal, etc.) pain, joint pain, dental pain and muscle pain. The term “pain” also includes pain of varying severity, i.e. mild, moderate and severe pain, as well as acute and chronic pain.
In traumatic or nociceptive pain, an external stimulus causes a normal sensory response to tissue damage associated with an insult or illness, and this sensation of pain is generally responsive to narcotic analgesics such as morphine; whereas in neuropathic pain, which results from injury to the nervous system, the sensation of pain is typically not responsive to narcotic analgesics. Neuropathic pain often involves neural hypersensitivity and can persist without any overt external stimulus (Goodman & Gilman's “The Pharmacologic Basis of Therapeutics”, 1996, 9th Ed., p. 529, McGraw-Hill).
The therapeutic objective of most pain therapy is to alleviate the symptoms of pain regardless of the cause. Current therapies include the use of opioid narcotic analgesics such as morphine and fentanyl, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen and cyclooxygenase inhibitors, or ion channel blockers such as lidocaine and novacaine. However, these therapies all have limitations. Opioids, for example, can cause tolerance, dependence, constipation, respiratory depression and sedation. NSAIDS can have gastrointestinal side effects and can increase bleeding time; in general, they are not effective in treating severe pain. Central nervous system (CNS) and cardiovascular side effects (Goodman & Gilman's “The Pharmacologic Basis of Therapeutics”, 9th Ed., 1996, p. 337, McGraw-Hill), as well as corneal damage are reported for the non-selective sodium channel blockers. Given these drawbacks to current therapies, there is clearly a need for better pain treatments.
Numerous published studies have documented the involvement of P2X nucleotide receptors in nociception. Activation of P2X receptors with agonists such as ATP or benzoylbenzoyl-ATP is associated with hyperalgesic action (Chizh and Illes, Pharmacol. Rev. 53:553-568 (2000); Jarvis and Kowaluk, Drug Development Res. 52:220-231 (2001)). Antagonism of P2X3 receptors by the ATP analog, ATP-TNP, has been shown to produce antinociceptive effects in rats (Jarvis and Kowaluk, 2001).
As described above, agents commonly used to treat pain may cause adverse side effects, and thus there is a continuing need for new agents that are both safe and effective in treating pain.